ToDo
drug substance that induces a response within the human body, whether beneficial or harmful (Ng, R. (2005a)) OTC <-> ethical new drugs <-> generics last 100 years Drug discovery Drug development Clinical trials Manufacturing Marketing Application laboratory->in vitro on animals->in vivo preclinical research activities optimized compound->potential drug GLP - Good Laboratory Practice US, Europe and Japan account for more than 85% of the worldwide pharmaceutical market. Choloesterol is an important constituent of the cell membrane and hormones ex vivo - outside the body approach to drug discovery can be classified as irrational rational antisense therapy gene therapy stem cell therapy @todo nucleotides when joined together make up the individual structurak units of the nucleic acids RNA, DNA rDNA cDNA gene photolithography proteins radioisotopes tetramer macromolecule is a very large molecule commonly created by polymerization the 4 conventional biopolymers nucleic acid proteins carbohydrates lipds macrocycles the individual constituents of polymers are monomers nucleotides molecules that when joined together make up the individual structural units of the nucleic acids RNA and DNA cellular signalling cGMP cAMP anzymatic reactions isomers are compounds with the same mocular formula, but different structural formulas functional groups specific groups of atoms and/or bonds within molecules that are responsible for the characteristic chemical reactions of these molecules steric effects arise from the face that each atom within a mocule occupies a certain amount of space. hinderance shielding attractions chain crossing repulsion ch2 ligands are molecules which bind to a target endogenous (produced by the body, eg hormones and neurotransmitters) exogenous (drug molecules, radioisotopes DNA microarray (dna chips, or gene chips) expressed sequence tags and in silico methods benzene is an organic chemical compound 6 carbon atoms in a ring, with 1 hydrgen atom attached to each carbon atomC6H6 the main drug targets of the human body are; enzymes intracellular receptors cell surface receptors transduced signal transduction is when the extracellular molecule actives a surface cell recptor which causes a second messenger to transmit the signaol into the cell http://en.wikipedia.org/wiki/Signal_transduction Cell Surface receptors these receptors have an affinity for hydrophobic binding molecules 3 main superfamilies -G-protein coupled receptors -ion channel receptors -catalytic receptors using enzymatic activities when the action of a drug is to activate or switch on a reaction, the drug is called an agonist with enzymes inducer inhibitor binding is specific binding occurs at particular sites in the target molecules binding is reversible allostieruc binding homotropic heterotrpoic covalent bonding electostatic interactions (hydrogen bonding or van der Waals forces) ibruprofen naproxen # enzymes almost all enzymes are proteins provide templates more favourable oriented to react enzymes have active sites E - potential energy barrier G - change in free energy enzymes can be assisted by coenzymes (cofactors) adenosine triphosphate (ATP) conformal shape change phosphorylation ## Tyrosine kinases class of receptor tranmsmits signals carried by hormomes and growth factors phosphorylation regulates most aspects of cell life dimerize ## intracellular receptors # Assay development when it not convenient or appropriate to use living system of the target receptor biochemical assays which mimic the target classical drugs are small artificial molecules which target proteins, enzymes and receptors # new uses for old drugs drug doscovery neglects diseases of the poor average of 15 years, and 800 million USD pharmokinetics Gaylordsville, Connecticut. phase 4 clinical studies cost 100 million USD per drug de novo drug discovery JHCCL wikipedia synthetic and natural products collection, nation cancer institute drugbank canada # natures bounty 80% of the worlds inhabitants rely on traditional medicines 119 chemical substances, that are derived from 90 plant species can be considered important drugs currently in use. penicillum notatum by fleming in 1929 less than 1% of bacterial species are known (American Academy of Microbiology) plant derived antocancer drugs alkaloids vinblastine and vincristine hypoglycaemic agents metabolites animal phyla chiral catalytic reactions monoclonal antibodies moiety (functional group) dark and middle ages (5th to 12th centory) the arabs were the first to establish privately owned drug stores alkaloid chemistry cardiotonic analgesic epothilone pharmacophores polyketide biosynthetic pathways keto-reduction amines tetracyclics aromatic polyketides by bacteria # A short introduction to molecular structure atoms consist of neutrons, protons and electrons there are about 120 known kings of atoms. each one with a name and a chemical symbol and by a number of protons, called the atomic number the atomic number of an atom is the number of protons in its nucleus it is also equal to the number of electrons in the neutral atom chemical elements are substances that consist puurely of atoms of the same atomic number ## Chemical compounds The empircal formulae tell us the ratio in which atoms are combined in compounds most chemical elements are metals ## molecular substances halogens dative bond resonance structure resonance hybrid benzene C6H6 dipole moment van der Waals forces much less strong than covalent bonding Hydrogen Bonding important in systems that contain water autoDeploy functional groups esters vs ethers electronegativity ## chemical bonding ### ionic and covalent bonding ionic compounds, ionic bonding when one electron is transferred to the other covalent bonding shared electron pair, gives rise to a molecular substance alectronegatvity is the power of its atoms to attract electrons to itself when forming chemical bonds ## Valency the number of lines emerging from some atom is equal to its valency structural formula of molecules bond pairs non bond pairs or lone pairs ### functional groups # introduction to stereochemistry ## the branch of chemistry dealing with the shapes of molecules is known as stereochemistry enzymes are classified in to 6 Oxidoreductases Transferases Hydrolases lysaea Osimerases Ligases allosteric binding site ## numerical constants that quantify drugs Km Kd IC50 Vmax rang et al 2012a c pharmacology p 99-114 # drug absorption and distribution ADME Absorption distribution Metabolism excretion bulk flow diffusion epithelial barrier periendothelium, features prevent harmful molecules from leaking leukocyte methods by which small molecules cross cell membranes diffusion diffusion through aqueous pores formed by special proteins by combination with a solute carrier pinocytosis mercurial reagents drug molecules usually exceed 1nm in diameter invagination permeability coefficient villi microvilli ileum Organic Anion Transporters (OATs) Organic Cation Transporters (OCTs) ester bonds concomitant means drugs that are given at the same, or almost the same time FOLFOX, a protocol for the treatment of colorectal cancer leucovorin Flourouracil Oxaliplatin Bioavailability and bioequivalence ezymes in the gut wall, the liver can deactivate drugs Hyperplasia increase in number of cells/proliferation of cells may result in the gross enlargement of an organ Hyperplasia is a common preneoplastic response to stimulus hyperplasia is considered to be a normal response to a specific stimuli an example of a normal hyperplastic repsonse would be growth of milk secreting gladular cells in response to pregnancy Neoplasia is an abnormal mass of tissue as a result of neoplasia metaplasia cell type conversion when cells are faced wiht physiological or pathological stress they respond by adapting in any of several ways there is a propensity for the irrated metaplastic region to turn cancerous of the stimulent is not removed. squamous cells pharmokinetics - what the body does to the drug pharmodynamics - what the drug does to the body ligand - chemical messenger Benzoapryrene - highly carcogenic mutagen found in coal tar with the formula C20H12 CYP enzymes have been identified in all domains of life, in animals, fungi, protists, bacteria, archaea, and even viruses knockout mice interpro is a database of protein families, domains and functional sites redox - reduction-oxidation substances with a ph of less than 7 are said to be acidic. acids react with bases arrhenius definition: Bronsted-lowry: an acid is a substance which can act as a proton donor ph is the negative logaritym ofthe if the concentration of hydronium ions http://en.wikipedia.org/wiki/Acid the free hydrogen nucleus does not exist along, hence H3O+ dimer - a molecule composed of 2 identical simpler molecules